Articular cartilage has poor reparative potential, but the reasons for this are not fully understood (Archer (1994) Ann. Rheum. Dis. 53, 624-630, Silver, et al. (1993) Otolaryngol. Clin. North Am. 28, 847-864). The lack of tissue vascularization and the putative absence of stem cells are potential explanations. Although histologic studies demonstrate the occurrence of chondrocyte death in response to mechanical injury, it is not fully known which stimuli trigger cell death and whether cell death occurs as apoptosis or necrosis (Calandruccio, et al. (1962) J. Bone Joint Surg. Am. 44A, 431-455, Mankin (1962) J. Bone Joint Surg. Am. 44A, 682-688, Bentley, et al. (1971) Nature 230, 385-388, Repo, et al. (1977) J. Bone Joint Surg. Am. 59A, 1068-1076). Cartilage, unlike other tissues, has no means of removing dead cells by phagocytosis due to the absence of tissue macrophages. Consequently, it may be proposed that lesions containing apoptotic or necrotic cells are detrimental, partly explaining poor integration with surrounding articular cartilage which is a common feature of most reported repair models. However, where this zone of cell death was resorbed by added macrophages, full repair has been reported (Joseph, et al. (1961) J. Anat. 95, 564-568).
Similarly, in marginal regions of injured meniscus where cell death was not observed, repair can be complete (Walmsley, et al. (1938) J. Anat. 12, 260-263). Collectively, these findings suggest that chondrocyte death may be one of the limiting factors in the response of cartilage to injury. However, information on the induction of cell death in response to mechanical injury is limited. It has recently been proposed that cell death in response to wounding is a combination of necrosis and apoptosis (Tew, et al. (2000) Arthritis Rheum. 43, 215-225). This distinction may be critical since apoptosis can be inhibited resulting in a potential increase in cell viability. Apoptosis has been inhibited in various settings (Rudel (1999) Herz. 124, 236-241).
Joint loading and motion can induce a wide range of metabolic responses in cartilage. Immobilization or reduced loading leads to a decrease in glycosaminoglycan (GAG) synthesis and content (Caterson, et al. (1978) Biochim. Biophys. Acta. 540, 412-422, Kiviranta, et al. (1987) Arthritis Rheum. 30, 801-809, Guilak (1994) J. Microsc. 173, 245-256, Sah, et al. (1989) J. Orthop. Res. 7, 619-636, Burton-Wurster, et al. (1993) J. Orthop. Res. 11, 717-729, Kim, et al. (1994) Arch. Biochem. Biophys. 311, 1-12). Increased dynamic loading causes an increase in GAG synthesis and content (Caterson, et al. (1978) Biochim. Biophys. Acta. 540, 412-422, Kirviranta, et al. (1987) Arthritis Rheum. 30, 801-809, Sah, et al. (1989) J. Orthop. Res. 7, 619-636, Gray, et al. (1988) J. Orthop. Res. 6, 777-792, Jones, et al. (1982) Clin. Orthop. 165, 283-289, Sah, et al. (1991) Arch. Biochem. Biophys. 286, 20-29). More severe static or impact loading causes cartilage deterioration and leads to osteoarthritic changes (Repo, et al. (1977) J. Bone Joint Surg. Am. 58A, 1068-1076, Gritzka, et al., J. Bone Joint Surg. Am. 55A, 1698-1720, Radin, et al. (1984) J. Orthop Res. 2, 221-234, Thompson, et al. (1991) J. Bone Joint Surg. Am. 73A, 990-1001). In fact, traumatic cartilage injury represents a major risk factor for the development of secondary osteoarthritis.
Prior histologic studies have demonstrated the occurrence of cell death after articular cartilage injury (Calandruccio, et al. (1962) J. Bone Joint Surg. Am. 44A, 431-455, Mankin (1962) J. Bone Joint Surg. Am. 44A, 682-688). More recently, cell death in response to articular cartilage wounding has been reported (Tew, et al. (2000) Arthritis Rheum. 43, 215-225). Electron microscopy and TUNEL evidence of both necrosis and apoptosis was seen in a band along the would margins. An increase in the band of cell death was observed over the first 5 days following the wounding. These phenomena were demonstrated in explants from bovine metacarpal and metatarsal joints with the production of a manually created cartilage defect. Clinically, accidental blunt trauma is by far the more common form of injury leading to cartilage lesions. Articular cartilage can sustain injury without apparent loss of matrix. It is possible that cell death (whether apoptotic or necrotic) may occur giving rise to later matrix degradation and the subsequent development of a full thickness cartilage lesion. Another recent study by Loening et al. demonstrated apoptosis after a similar injurious loading of cartilage explants (Loening, et al. (2000) Arch. Biochem. Biophys. 381, 205-212). Recently, broad spectrum caspase inhibitors and selective non-peptide caspase inhibitors have been successfully used to inhibit apoptosis induced by several agents in cultured human chondrocytes (Lee, et al. (2000) J. Biol. Chem. 275, 16007-16014, Nuttal, et al., (2000) J. Orthop. Res. 18, 356-363). In the setting of mature articular cartilage with a limited source of chondrocytes, maintaining viability could substantially impact subsequent degeneration and repair.
The experimental models used in most prior studies are not especially useful in predicting clinical outcomes. There is a need therefore for clinically relevant studies disclosing the mechanisms underlying cell death in injured cartilage. The model used in the current study was chosen to represent a type of blunt trauma that is more clinically relevant.